Ethyl fumarate preparation

Ethyl fumarate has been prepared from fumaric acid and ethyl alcohol, with or without sulfuric acid as catalyst,4 from silver fumarate and ethyl iodide,5 from silver maleate and ethyl iodide plus a trace of iodine,6 from ethyl maleate by the action of iodine,6 from ethyl maleate and phosphorus pentachloride,7 and by passing hydrogen chloride into a boiling absolute alcohol solution of malic acid.8... 

If 99 per cent alcohol is used instead of 96 per cent, the yield of ethyl fumarate is 87 per cent of the theoretical instead of 80 per cent. When large quantities of ester are being prepared it is easy to use dry alcohol, since the alcohol-water distillate can be dehydrated over quicklime and used again. The wet alcohol is conveniently dehydrated by refluxing six hours over quicklime in a 12-I. flask and then distilling. 

The results under flow conditions showed a slight improvement in nearly all areas compared with the representative batch reaction - importantly, both the yield and chemoselectivity were significantly improved - but all reactions still produced a significant amount of the dimerized by-products (ethyl fumarate (57) and ethyl maleate (58)). The solventless system allowed larger quantities of material to be prepared, whereas the scC02 system provided products contaminated with only traces of ruthenium (less than 1 ppm). 

Ethoxy-4-methyloxaole has been used to form pyridoxine (MI-286, R = H). With maleic anhydride it gives an adduct that, on treatment with ethanolic hydrogen chloride, forms the products W-287 and XII-288 (R = R - Et) and a monoester (XII-288 R = Et, R = H or R = H, R = Et). The diethyl ester MI-288 is also formed from ethyl maleate or ethyl fumarate and 5-ethoxy-4-methyloxazole. Fumaronitrile and ethoxy-4inethyloxazol ve 4,5-dicyano-2-methyl-3-pyridinol, ° also a known precursor to pyridoxine. 5-Ethoxy 4-irethyloxaolesand 2-butene-1,4-diol give pyridoxine (XII-286, R = H), which is difficult to purify when prepared in this way (assay, 23%). 

The procedure described is essentially that of Ballard and Dehn.1 Stilbene has also been prepared by reduction of desoxy-benzoin,20 benzaldehyde,23 and benzil 2o-2c by dehydrogenation of ethyl benzene,30 toluene,30- 33- 3, and bibenzyl 33-3alkaline reduction of phenylnitromethane,40 phenylnitroacetonitrile,40 and desoxybenzoin 43 by distillation of benzyl sulfone,50 benzyl sulfide,60-63 calcium cinnamate,5 cinnamic acid,5d phenyl cinna-mate,6e-6/ and diphenyl fumarate ie by dehydrohalogenation of a,a -dichlorobibenzyl60 and benzyl chloride 63 by dehalogenation of a,a,c/,a -tetrachlorobibenzyl70 and benzal chloride 73 by the coupling of cinnamic acid and phenyldiazonium chloride 8 by de-... 

The formation of carbanions, according to Scheme 6, has been much studied but has proved to be of little preparative use. The benzyl anion, generated from benzyl-dimethylsulphonium tosylate, reacted with acrylonitrile but the addition product was formed in only low yield Similarly the reactive ylid formed by deprotonation of trimethylsulphonium salts has been cathodically generated and trapped by several aldehydes and ketones as well as ethyl maleate and fumarate examples are given in Scheme 7. For the best case (benzophenone), the epoxide was formed in 40%... 

Other preparations of 2-iminothiazolidin-4-ones which are discussed in the review by Brown139 utilize the reactions of thiourea with a-hydroxy acids,146 ethyl diazoacetate,73 glycidic esters,74,147 cinnamic acid,148 unsaturated diacids (fumaric, maleic, and citraconic) or their esters or imides,149-152 and propiolic esters.153,154 There has been considerable controversy in the literature surrounding the propiolic ester synthesis since many workers have proposed that the products are 1,3-thiazines (see Section IV, B, 1). The pertinent papers in this controversy have been summarized by Cain and Warrener.155 Nagase158 has recently settled the argument in favor of the 2-iminothiazolidin-4-... 

Pyrazino[l,2-c]pyrimidines are most commonly prepared from the intermediate 1-alkyl-3-(2-alkylaminoethyl)piperazines (281). This intermediate is readily prepared in three steps from either benzyloxycarbonylsarcosylaspartate (71JMC929) or from iV-benzylethyl-enediamine and diethyl fumarate (75JMC913). Condensation of the piperazine intermediate (281) with ethyl chloroformate at pH 3-3.5 gives the monocarbamates (282). Cyclization of these carbamates by treatment with sodium ethoxide gives the desired ring system (283) (75JMC913). 

Now that fumaric and maleic acid are available commercially, the most convenient method of preparing the above ester consists in condensing ethyl malonate with ethyl fumarate1 or ethyl maleate.2 It has also been prepared by condensing malonic ester with ethyl chlorosuccinate 3 and with ethyl ethoxysucci-nate.4... 

Methyl-l-piperazinyl)benzimididazole (5.00 g) prepared as above is dissolved in N,N-dimethylformamide (50 ml) and thereto is added sodium hydride (concentration 50%) (1.50 g) at room temperature, and the mixture is stirred for 30 minutes. To the mixture is added 2-bromoethyl ethyl ether (4.00 g), and the mixture is stirred at 70°C for 10 hours. To the reaction mixture is added water (150 ml), and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a brown oily substance (5.40 g). The brown oily substance is treated with fumaric acid (3.26 g) in hot ethanol. The crude crystals thus obtained are recrystallized from ethyl acetate-ethanol to give l-[2-(ethoxy)ethyl]-2-(4-methyl-l-piperazinyl)benzimidazole 3/2 fumarate (6.31 g) as colorless plates, melting point 167.5°-168.5°C. Elementary analysis for C22H30N4O7 Calcd. (%) C, 57.13 H, 6.54 N, 12.11 Found (%) C, 57.04 H, 6.44 N, 12.02. 

Preparation of 2- (3S)-3-[(2-naphthylsulfonyl)amino]-2-oxopiperidyl -iV-[2-(amidinoaminooxy)ethyl]acetamide fumaric acid... 

Following the key finding of Helmchen [23], the bis-(S)-ethyl lactate ester of fumaric acid was prepared from fumaryl chloride, as illustrated in Scheme 2. Cycloaddition of this dienophile with cyclopentadiene to give (3) required some experimental modification in order to eliminate halogenated solvents. A survey of solvents and reaction conditions revealed that triethylamine as solvent allows both a reasonable reaction rate and high diastereomeric excess (d.e. = 93%) when the reaction is conveniently conducted at room temperature. 

Nitrile sulfides are well suited for the synthesis of isothiazoles incorporating the C=N-S unit via their 1,3-dipolar cycloaddition reactions with double or triple-bonded dipolarophiles. Benzonitrile sulfide 210 is readily prepared from decarboxylation of oxathiazolone 209 using microwave irradiation <05SC807>. Subsequent cycloadditions to dimethyl acetylene-dicarboxylate (DMAD) and dimethyl fumarate afford 211 and 212, respectively. In the case of ethyl propiolate, a 1 1 regioisomeric mixture of phenylisothiazoles 213 and 214 is obtained. 

Full details for the preparation of ethyl 4-hydroxycrotonate [ (243) R=H] from monoethyl fumarate have been given. The... 

Diester derivatives of maleic and fumaric acid (see Chapter 3) are not easily polymerized. However, they do yield soft, tacky thermoplastics with free-radical generating initiators such as BPO. Diethyl fumarate, for example, polymerizes to an 89% yield of poly (ethyl succinate) when heated in the presence of 2% BPO for 7 Liquid-phase (neat) reaction at high pressure (5000 psi) improves the yield.Polymers of higher softening point and higher molecular weight may be prepared by emulsion-polymerization techniques. 

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